The field of the invention is cancer-specific antigens.
Individuals with cancer frequently exhibit elevated levels of circulating antigens which are associated with that cancer. Such is the case in women with breast carcinoma. A monoclonal antibody (MAb) was prepared against a membrane-enriched extract of a human breast carcinoma metastatic to liver (Kufe et al., 1984, Hybridoma 3:223-232). The antibody was specific for what was termed DF3 antigen, a human breast carcinoma-associated antigen that is a collection of closely related, high molecular weight glycoproteins having the common property that they react with anti-DF3 antibodies. DF3 antigen is also described in U.S. Pat. No. 4,963,484 and in U.S. patent application Ser. No. 174,838, (now abandoned) both of which are herein incorporated by reference. DF3 antigen is detectable on the apical borders of normal secretory mammary epithelial cells and in the cytosol of less differentiated malignant breast cells (Kufe et al., 1984, Hybridoma 3:223-232). This apical and cytoplasmic staining pattern has also been described for MAbs prepared against human milk fat globule membranes (HMFGM) and breast carcinoma cell lines (Arklie et al., 1981, Int. J. Cancer 28:23-29; Hilkens et al., 1984, Int. J. Cancer 34:197-206; Sloane et al., 1981, Cancer 47:1786-1795; Croghan et al., 1983, Cancer Res. 43:4980-4988). Because DF3 antigen is detectable at elevated levels in the plasma of women with metastatic breast cancer, it has been used to monitor clinical course (Hayes et al., 1986, J. Clin. Oncol. 4:1542-1550; Tondini et al., 1988, Cancer Res. 8:4107-4122; Perey et al., 1990, Br. J. Cancer 62:668-670). Expression of this antigen has also been correlated with the degree of breast tumor differentiation and estrogen receptor status (Lundy et al., 1985, Br. Cancer Res. Treat. 5:269-276).
The finding that expression of DF3 in breast carcinoma cells and human milk is heterogenous suggested the possibility of a genetic polymorphism (Sekine et al., 1985, J. Immunol. 135:3610; Hilkens et al., 1989, Cancer Res. 49:786; Karlsson et al., 1983, Ann. Hum. Genet. 47:263). Indeed, studies in family members demonstrated that the electrophoretic heterogeneity of DF3 antigen is determined by codominant expression of multiple alleles at a single locus (Hayes et al., 1988, Blood 71:436). Sequence analysis of cDNA clones coding for this protein revealed highly conserved (G+C)-rich 60 base-pair tandem repeats (Swallow et al., 1987, Nature 328:82; Siddiqui et al., 1988, Proc. Natl. Acad. Sci. USA 85:2320; Gendler et al., 1988, J. Biol. Chem. 263:12820). These repeats code for epitopes recognized by MAb DF3, as well as other MAbs such as one termed SM-3 (Burchell et al., 1987, Cancer Res. 47:5476), prepared against the intact glycoprotein and the unglycosylated protein core (Siddiqui et al., 1988, Proc. Natl. Acad. Sci. USA 85:2320; Gendler et al., 1988, J. Biol. Chem. 263:12820; Burchell et al., 1987, Cancer Res. 47:5476). Moreover, these antibodies react with certain synthetic peptides prepared according to the in-frame sequence of the tandem repeat (Gendler et al., 1988, J. Biol. Chem. 263:12820; Abe and Kufe, 1989, Cancer Res. 49:2834).